Kinetic resolution

ABSTRACT

Whilst methodologies for the Kinetic Resolution of alcohols are well established, no analogous direct methods exist for the highly selective, direct catalytic Kinetic Resolution of thiols (i.e., R—SH). The present invention relates to a method for resolving stereoisomeric mixtures of thiols. In particular, the present invention relates to purely organocatalytic mediated resolution of enantiomeric mixtures of thiols without the need for enzymes. Also disclosed are some novel catalysts. Such catalysts may comprise a cinchona alkaloid-derived moiety.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 13/515,092 filed on Jun. 11, 2012, which is a 371 of InternationalPatent Application No. PCT/EP2010/069097 filed on Dec. 7, 2010, whichclaims the benefit of priority of European Patent Application No.09178565.9 filed on Dec. 9, 2009, the entire contents of which areincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a method for resolving stereoisomericmixtures of thiols. In particular, the present invention relates topurely organocatalytic mediated resolution of enantiomeric mixtures ofthiols without the need for enzymes. Also disclosed are some novelcatalysts.

BACKGROUND TO THE INVENTION

Kinetic resolution (KR) is an established methodology for thepreparation of enantioenriched compounds (see Scheme 1). In a chiralenvironment, for example in the presence of a chiral reagent B*, theenantiomers of a racemic mixture (A and A′) exhibit different reactionkinetics making it possible to modify one enantiomer (e.g. to provideA-B*) of the racemic mixture preferentially over the other. Thus, bypreferentially modifying one of the enantiomers it is easy to separateit from the other enantiomer.

KR represents one of the most convenient methods for the rapid isolationof enantiopure alcohols by resolving the corresponding racemic materialsvia enantioselective acylation as shown in Scheme 2.

Initially, KR of racemic alcohols was carried out using biologicalcatalysts such as enzymes. However, enzyme mediated catalysis can betroublesome on account of the low tolerance of enzymes to changes in pHand temperature. Furthermore, the incompatibility of enzymes withorganic solvents vastly reduces the range of alcohol substrates that aresuitable for acylation via enzyme mediated catalysis. Accordingly, inrecent years several efficient and selective artificial organocatalystsfor these processes have become available. As used hereinorganocatalysts are small molecule, non-metal containing catalysts thatare soluble in organic solvents.

While the KR of alcohols is now a mature and useful technology, noanalogous direct methods exist for the highly selective, directcatalytic KR of racemic thiols (i.e., R—SH)—despite the importance ofthiols and organosulfur compounds in organic chemistry, and chemicalbiology.

Baker's yeast has been used to resolve a chiral thiol in the presence ofglucose, however the resolved material was isolated in trace amountsonly and with low enantioselectivity (40% ee). Reports disclosinglipase-catalysed transesterification of thioesters derived from racemicthiols are also acknowledged. Under optimal conditions the thiolproducts were obtained with high enantioselectivity (up to 95% ee).However, the latter is a multi-step methodology for the KR of thiols,only three thioester substrates were resolved, the methodology requiredlong reaction times (up to 200 h) and high mass loadings of the enzymecatalyst.

International Patent Publication No. WO2009/050216 discloses amethodology for the dynamic kinetic resolution of thiols comprisingutilising a hydrolase enzyme in the presence of an epimerisationcatalyst. Notwithstanding these reports, enzymatic mediated resolutionof thiols intrinsically suffers from the same problems as enzymaticresolution of alcohols discussed above.

While enantioenriched thiols can be synthesised from the correspondingalcohols, this simply makes one reliant on (and limited by) theavailability of the desired alcohol substrate in enantiopure form. Inaddition, care must be exercised where a substrate (or its derivatives)is capable of racemisation.

For example, in attempting to prepare enantiopure thiols from thecorresponding alcohols the present inventors found that subjectingcommercially available (R)-1-phenyl-2-methyl-propanol (>99% ee) to asequence involving mesylation, substitution with thioacetate ion (dryDMSO solvent, rt) and deprotection with LiAlH₄ afforded(S)-1-phenyl-2-methyl-propanethiol in a substantially diminishedenantiomeric excess of 84.5%, despite considerable care taken to try toavoid conditions favoring a competing SN1 substitution pathway (seeScheme 3).

The paucity of methodologies available for the catalytic asymmetricsynthesis of enantioenriched thiols, and for the KR of thiols inparticular, is attributable to the fact that, relative to alcohols,thiol substrates are inter alia ‘softer’ nucleophiles, exhibit greateratomic distance between the reacting heteroatom and the stereocenter andpossess a lower heteroatom pKa.

Accordingly, it would be desirable to provide an organocatalyticenantioselective acylation protocol for the kinetic resolution ofthiols, which mitigates the problems disclosed supra.

SUMMARY OF THE INVENTION

The present invention provides for a method for resolving stereoisomericmixtures of thiols. In particular, the present invention provides forpurely organocatalytic mediated resolution of enantiomeric mixtures ofthiols without the need for enzymes. Advantageously, such a method wouldnot suffer from incompatibilities with organic solvents, high/lowtemperatures, high/low pH, etc. as discussed above.

Accordingly, in a first aspect the present invention provides for amethod of resolving a mixture of stereoisomers of a thiol comprising thestep of preferentially acylating one thiol stereoisomer in the presenceof a bifunctional organocatalyst.

A mixture of stereoisomers of a thiol may comprise either enantiomericmixtures or diastereomeric mixtures of the thiol. The mixture ofstereoisomers of a thiol may be a diastereomeric mixture of the thiol.There is no upper limit on the number of diastereomers in the mixture,for example there could be between four and ten diastereomers within themixture. The mixture of stereoisomers of a thiol may be an enantiomericmixture of the thiol, i.e. a mixture consisting of two enantiomers.

As used herein the term mixture does not limit to a two component mix ora specific ratio of two or more components. In particular it does notlimit to a 50:50 mixture. Mixture ratios from 1:99 to 99:1 are coveredby the term mixture. The term mixture also covers multi componentmixtures, such as a mixture of 3 or more diastereomers in any givenratio.

Within this specification, the term bifunctional organocatalyst refersto a chiral, small organic molecule (i.e., non-metal based) having aLewis acid moiety and a Lewis base moiety within the molecule, which isused in sub-stoichiometric loading relative to at least one of thereactants. The chiral, small organic molecule may comprise between 5 and60 carbon atoms. The bifunctional organocatalyst may be used insubstoichiometric loading relative to the stereoisomeric mixture of thethiol.

Suitably, the bifunctional organocatalyst or chiral small organicmolecule is substantially enantiopure. This is important for efficientresolution (or separation) of the mixture of stereoisomers. Thebifunctional organocatalyst may function by enhancing thenucleophilicity of a first reaction component and enhancing theelectrophilicity of a second reaction component. For example, thebifunctional organocatalyst may enhance the electrophilicity of anacylating agent (such as an organic anhydride) and enhance thenucleophilicity of one enantiomer of an enantiomeric mixture of a thiol,thereby facilitating reaction of both components in a chiralenvironment.

The thiols may be selected from the group consisting of primary thiolsand secondary thiols. The thiol may be a thiol selected from the groupconsisting of C₁-C₁₀₀ alkyl, C₃-C₁₀₀ cycloalkyl, C₅-C₁₀₀ aryl, C₅-C₁₀₀heteroaryl and combinations thereof. The thiol may be a secondary thiol.The secondary thiol may be selected from the group consisting of C₁-C₁₀₀alkyl, C₃-C₁₀₀ cycloalkyl, C₅-C₁₀₀ aryl, C₅-C₁₀₀ heteroaryl andcombinations thereof. The secondary thiol may be selected from the groupconsisting of C₁-C₂₀ alkyl, C₅-C₂₀ aryl and combinations thereof. Thethiol may be optionally substituted one or more times with at least oneof a halogen, C₁-C₅ alkoxy, C₁-C₅ thioalkoxy, and cyano.

As used herein, the term “C_(x)-C_(y) alkyl” embraces C_(x)-C_(y)unbranched alkyl, C_(x)-C_(y) branched alkyl and combinations thereof.The term (cyclo)alkyl does not preclude the presence of one or more C—Cunsaturated bonds in the carbon (ring)/chain. The terms aryl andheteroaryl encompass fused aromatic and fused heteroaromatic ringsrespectively.

The method of the present invention may be carried out in a solventselected from the group consisting of C₅-C₁₂ hydrocarbons, C₆-C₁₂aromatic hydrocarbons, C₃-C₁₂ ketones (cyclic and acyclic), C₂-C₁₂ethers (cyclic and acyclic), C₂ to C₁₂ esters (cyclic and acyclic),C₂-C₅ nitriles and combinations thereof. Desirably, the solvent isethereal. For example, C₂-C₁₂ ethers (cyclic and acyclic). Suitableethers may be selected from the group consisting of diethylether, THF,2-methyl THF, diisopropylether, methyltertbutylether (MTBE) andcombinations thereof. In a preferred embodiment, the solvent ismethyltertbutylether (MTBE).

The catalyst loading with respect to the thiol may be 0.1-50 mol %, forexample 0.1-25 mol %, such as 0.1-10 mol %. Desirably, the catalystloading with respect to the thiol is 5-10 mol %. Advantageously, thisrepresents a highly economic and efficient catalyst loading.

The bifunctional organocatalyst may comprise a cinchona alkaloid. Asused herein a catalyst comprising a cinchona alkaloid refers to anycatalyst comprising one of the following structural elements:

Z can be a C₁ to C₅ carbon chain optionally comprising at least one C—Cunsaturated bond, and optionally substituted one or more times with atleast one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester,C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide and combinations thereof;

M can be H, OH, or OMe; and

R₁ is a moiety comprising a hydrogen bond donor.

The moiety comprising a hydrogen bond donor may comprise between 1 and30 carbon atoms. The cinchona alkaloid may be substituted with a urea,thiourea or sulfonamide functional group. For example, R₁ may comprise aurea, thiourea or sulfonamide functional group. For example, R₁ maycomprise a C₁-C₂₀ urea, C₁-C₂₀ thiourea or a C₁-C₂₀ sulfonamide.

The bifunctional organocatalyst may be selected from the groupconsisting of:

wherein X can be O or S;

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof;    -   M can be H, OH, or OMe;    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₁ and R₂ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₁ and R₂ may together define a C₃-C₁₅ cycloalkyl ring        (i.e., R₁ and R₂ may together with N define a C₃-C₁₅        heterocyclic ring), wherein each may be optionally substituted        one or more times with at least one of a halogen, cyano, CF₃,        NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone,        C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₃ and R₄ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₃ and R₄ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof; and    -   R₅ and R₆ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₅ and R₆ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof.

As used herein “Bn” is short hand for “benzyl”.

The bifunctional organocatalyst may be selected from the groupconsisting of:

-   -   wherein Z can be a C₁ to C₅ carbon chain optionally comprising        at least one C—C unsaturated bond, and optionally substituted        one or more times with at least one of a halogen, cyano, CF₃,        NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone,        C₁-C₅ sulfoxide and combinations thereof;    -   M can be H, OH, or OMe;    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₁ and R₂ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₁ and R₂ may together define a C₃-C₁₅ cycloalkyl ring        (i.e., R₁ and R₂ may together with N define a C₃-C₁₅        heterocyclic ring), wherein each may be optionally substituted        one or more times with at least one of a halogen, cyano, CF₃,        NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone,        C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; and    -   R₃ and R₄ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₃ and R₄ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof.

B may be C₅-C₁₅ aryl, or C₅-C₁₅ heteroaryl optionally substituted one ormore times with at least one of a halogen, C₁-C₅ alkyl, or combinationsthereof.

The bifunctional organocatalyst may be selected from the groupcomprising:

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof;    -   M can be H, OH, or OMe; and    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof.

B may be C₅-C₁₅ aryl, or C₅-C₁₅ heteroaryl optionally substituted one ormore times with at least one of a halogen, C₁-C₅ alkyl, or combinationsthereof.

According to the method of the present invention the step of acylatingthe thiol comprises reacting the thiol with an organic anhydride. Theorganic anhydride may be a cyclic anhydride. The organic anhydride(cyclic or acyclic) may be a C₄-C₅₀ organic anhydride.

The organic anhydride may be selected from the group consisting of:

wherein R₁ and R₂ are the same or different and are selected from thegroup consisting of C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀heteroaryl and combinations thereof, optionally substituted with atleast one of a halogen, cyano, or C₁-C₅ fluoroalkyl;

R₃ and R₄ are the same or different and are selected from the groupconsisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀heteroaryl and combinations thereof, optionally substituted with atleast one of a halogen, cyano, or C₁-C₅ fluoroalkyl, such that at leastone of R₃ and R₄ is H;

R₅ and R₆ are the same or different and are selected from the groupconsisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀heteroaryl and combinations thereof, optionally substituted with atleast one of a halogen, cyano, or C₁-C₅ fluoroalkyl; and

n can be 0-5.

The organic anhydride may be of the general formula:

-   -   and may be a prochiral anhydride, wherein R₃ and R₄ are the same        or different and are selected from the group consisting of H,        C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀ heteroaryl        and combinations thereof, optionally substituted with at least        one of a halogen, cyano, or C₁-C₅ fluoroalkyl, such that at        least one of R₃ and R₄ is H; and    -   n is 1.

According to the method of the present invention acylation of the thiolwith the prochiral anhydride in the presence of the bifunctionalorganocatalyst may proceed with desymmetrisation of the prochiralanhydride to afford a thioester. The thioester may be at least one ofenantiomerically or diastereomerically enriched.

The organic anhydride may be of the general formula:

-   -   and may be a meso anhydride, wherein R₅ and R₆ are the same and        are selected from the group consisting of H, C₁-C₂₀ alkyl,        C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀ heteroaryl and        combinations thereof, optionally substituted with at least one        of a halogen, cyano, or C₁-C₅ fluoroalkyl.

According to the method of the present invention acylation of the thiolwith the meso anhydride in the presence of the bifunctionalorganocatalyst may proceed with desymmetrisation of the meso anhydrideto afford a thioester. The thioester may be at least one ofenantiomerically or diastereomerically enriched.

In a further aspect, the present invention provides for use of themethod of the present invention in the preparation of an enantioenrichedthiol. The enantioenriched thiol may be a pharmaceutical. For example,the method of the present invention may be used in the preparation ofenantioenriched 3-(aminomethyl)-5-methylhexanoic acid. The(R)-enantiomer of 3-(aminomethyl)-5-methylhexanoic acid is theblockbuster anti-convulsive drug Pregabalin marketed as ‘Lyrica’®.

In yet a further aspect the present invention provides for a process forthe preparation of enantioenriched 3-(aminomethyl)-5-methylhexanoic acidcomprising the steps of:

-   -   preferentially acylating one thiol enantiomer of an enantiomeric        mixture of the thiol with 3-isobutylglutaric anhydride in the        presence of a bifunctional organocatalyst according to the        method of the present invention; and    -   converting the thioester functional group (formed in the        previous step) into an amine.

The step of converting the thioester functional group into an amine maycomprise:

-   -   i) aminolysis of the thioester functional group to yield an        amide; and    -   ii) subjecting the amide product of step i) to a Hofmann        rearrangement.

Aminolysis of the thioester functional group may comprise treating thethioester with ammonia or an amine. Preferably, aminolysis of thethioester functional group comprises treating the thioester with ammoniato yield a primary amide. The Hofmann rearrangement is an eminentsynthetic transformation which converts an amide to an amine with theloss of carbon monoxide. All protocols for effecting this transformationare embraced by the present invention.

The invention further provides for a compound having the generalstructure:

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof; and    -   M can be H, OH, or OMe.

The compound of the present invention may be used as an acylationcatalyst in the resolution of a mixture of stereoisomers of a thiol.That is a molecule that catalyses preferential acylation of one thiolstereoisomer over another thiol stereoisomer. Desirably, the mixture ofstereoisomers of a thiol is an enantiomeric mixture of the thiol.

In a further aspect the present invention provides for a method ofdesymmetrising at least one of a prochiral anhydride or a meso anhydridecomprising the steps of:

-   -   (i) adding the prochiral anhydride or meso anhydride to a        mixture of enantiomeric thiols; and    -   (ii) adding a bifunctional organocatalyst to the mixture of the        prochiral anhydride and the enantiomeric thiols.

The prochiral anhydride may be a C₆-C₄₀ anhydride. The meso anhydridemay be a C₆-C₄₀ anhydride. The prochiral anhydride may be of the generalformula:

-   -   wherein R₃ and R₄ are the same or different and are selected        from the group consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl,        C₅-C₂₀ aryl, C₅-C₂₀ heteroaryl and combinations thereof,        optionally substituted with at least one of a halogen, cyano, or        C₁-C₅ fluoroalkyl, such that at least one of R₃ and R₄ is H; and    -   n is 1.

The meso anhydride may be of the general formula:

-   -   wherein R₅ and R₆ are the same and are selected from the group        consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl,        C₅-C₂₀ heteroaryl and combinations thereof, optionally        substituted with at least one of a halogen, cyano, or C₁-C₅        fluoroalkyl.

The thiols may be selected from the group consisting of primary thiolsand secondary thiols. The thiol may be a thiol selected from the groupconsisting of C₁-C₁₀₀ alkyl including C₃-C₁₀₀ cycloalkyl, C₅-C₁₀₀ arylincluding C₅-C₁₀₀ heteroaryl and combinations thereof. The thiol may bea secondary thiol. The secondary thiol may be selected from the groupconsisting of C₁-C₁₀₀ alkyl including C₃-C₁₀₀ cycloalkyl, C₅-C₁₀₀ arylincluding C₅-C₁₀₀ heteroaryl and combinations thereof. The secondarythiol may be selected from the group consisting of C₁-C₂₀ alkyl, C₅-C₂₀aryl and combinations thereof. The thiol may be optionally substitutedone or more times with at least one of a halogen, C₁-C₅ alkoxy, C₁-C₅thioalkoxy, and cyano.

The bifunctional organocatalyst may comprise a cinchona alkaloid. Forexample, the catalyst may comprise one of the following structuralelements:

Z can be a C₁ to C₅ carbon chain optionally comprising at least one C—Cunsaturated bond, and optionally substituted one or more times with atleast one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester,C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide and combinations thereof;

M can be H, OH, or OMe; and

R₁ is a moiety comprising a hydrogen bond donor.

The moiety comprising a hydrogen bond donor may comprise between 1 and30 carbon atoms. The cinchona alkaloid may be substituted with a urea,thiourea or sulfonamide functional group. For example, R₁ may comprise aurea, thiourea or sulfonamide functional group. For example, R₁ maycomprise a C₁-C₂₀ urea, C₁-C₂₀ thiourea or a C₁-C₂₀ sulfonamide.

The bifunctional organocatalyst may be selected from the groupconsisting of:

wherein X can be O or S;

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof;    -   M can be H, OH, or OMe;    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₁ and R₂ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₁ and R₂ may together define a C₃-C₁₅ cycloalkyl ring        (i.e., R₁ and R₂ may together with N define a C₃-C₁₅        heterocyclic ring), wherein each may be optionally substituted        one or more times with at least one of a halogen, cyano, CF₃,        NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone,        C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₃ and R₄ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₃ and R₄ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof; and    -   R₅ and R₆ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₅ and R₆ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof.

The bifunctional organocatalyst may be selected from the groupconsisting of:

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof;    -   M can be H, OH, or OMe;    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof;    -   R₁ and R₂ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₁ and R₂ may together define a C₃-C₁₅ cycloalkyl ring        (i.e., R₁ and R₂ may together with N define a C₃-C₁₅        heterocyclic ring), wherein each may be optionally substituted        one or more times with at least one of a halogen, cyano, CF₃,        NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone,        C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; and    -   R₃ and R₄ can be the same or different and may comprise C₁-C₁₅        alkyl, or R₃ and R₄ may together define a C₃-C₁₅ cycloalkyl        ring, a C₅-C₁₅ aryl ring, or a C₅-C₁₅ heteroaryl ring wherein        each may be optionally substituted one or more times with at        least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅        ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl        and combinations thereof.

B may be C₅-C₁₅ aryl, or C₅-C₁₅ heteroaryl optionally substituted one ormore times with at least one of a halogen, C₁-C₅ alkyl, or combinationsthereof.

The bifunctional organocatalyst may be selected from the groupcomprising:

-   -   Z can be a C₁ to C₅ carbon chain optionally comprising at least        one C—C unsaturated bond, and optionally substituted one or more        times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅        ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide and combinations thereof;    -   M can be H, OH, or OMe; and    -   B can be C₁-C₁₅ alkyl, C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅        heteroaryl or combinations thereof, optionally substituted one        or more times with at least one of a halogen, cyano, CF₃, NO₂,        C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅        sulfoxide, C₁-C₅ alkyl and combinations thereof.

B may be C₅-C₁₅ aryl, or C₅-C₁₅ heteroaryl optionally substituted one ormore times with at least one of a halogen, C₁-C₅ alkyl, or combinationsthereof.

The method of the present invention may be carried out in a solventselected from the group consisting of C₅-C₁₂ hydrocarbons, C₆-C₁₂aromatic hydrocarbons, C₃-C₁₂ ketones (cyclic and acyclic), C₂-C₁₂ethers (cyclic and acyclic), C₂ to C₁₂ esters (cyclic and acyclic),C₂-C₅ nitriles and combinations thereof. Desirably, the solvent isethereal. For example, C₂-C₁₂ ethers (cyclic and acyclic). Suitableethers may be selected from the group consisting of diethylether, THF,2-methyl THF, diisopropylether, methyltertbutylether (MTBE) andcombinations thereof. In a preferred embodiment, the solvent ismethyltertbutylether (MTBE).

The catalyst loading with respect to the thiol may be 0.1-50 mol %, forexample 0.1-25 mol %, such as 0.1-10 mol %. Desirably, the catalystloading with respect to the thiol is 5-10 mol %. This represents ahighly economic and efficient catalyst loading.

The compounds resolved by the present invention may be found or isolatedin the form of esters, salts, hydrates or solvates—all of which areembraced by the present invention.

Where suitable, it will be appreciated that all optional and/orpreferred features of one embodiment of the invention may be combinedwith optional and/or preferred features of another/other embodiment(s)of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Additional features and advantages of the present invention aredescribed in, and will be apparent from, the detailed description of theinvention and from the drawings in which:

FIG. 1 illustrates Kinetic Resolution of a thiol with simultaneousenantioselective synthesis of a (R)-Pregabalin precursor.

FIG. 2 depicts a chromatogram of the thioesters 7a-b (derivatised astheir o-nitrophenyl esters for analysis via CSP-HPLC) from the reactionof 1 with 3 in the presence of triethylamine and an achiral thiourea ascatalysts.

FIG. 3 depicts a chromatogram of the thioesters 7a-b (derivatised astheir o-nitrophenyl esters for analysis via CSP-HPLC) from the reactionof (S)-1 (84.5% ee) with 3 in the presence of triethylamine and anachiral thiourea as catalysts.

FIG. 4 depicts a chromatogram of the thioesters 7a-b (derivatised astheir o-nitrophenyl esters for analysis via CSP-HPLC) from the reactionof 1 with 3 in the presence of catalyst 18 in MTBE at −30° C.

DETAILED DESCRIPTION OF THE INVENTION

It should be readily apparent to one of ordinary skill in the art thatthe examples disclosed herein below represent generalised examples only,and that other arrangements and methods capable of reproducing theinvention are possible and are embraced by the present invention.

Preliminary experiments related to the acylative KR of the racemicsec-thiol 1 with glutaric anhydride (2a) in the presence of bifunctional(thio)urea-derived organocatalysts 10-12 and sulphonamide 13 (Table 1).Initial results were far from encouraging—acylation proceeded smoothlyat low catalyst loading (5 mol %), but resulted in products of lowenantiomeric excess (entries 1-4). Of the four catalysts testedsulphonamide 13 proved superior to the (thio)urea-derivatives and couldpromote the KR with a very modest selectivity (k_(fast)/k_(slow)) of 1.5(13% ee at 50% conv., entry 4). Further experimentation identifiedmethyl tert-butylether (MTBE) as the optimal solvent overall, althoughthe KR of 1 was slower but more selective in THF (entries 4-7).

These results represented the first examples of direct catalyticasymmetric KR of a thiol. Subsequently, KR reactions using 3-substitutedachiral anhydride electrophiles 3a-5 were tried. This complicatedmatters considerably, as now control over the formation of 4 possiblethioester diastereomers is required. In addition, it allowed for thepossibility of a conceptually novel type of catalytic process where bothkinetic resolution and anhydride desymmetrisation occur simultaneously.Gratifyingly, this proved to be the case—use of anhydrides 3a-5 resultedin more enantioselective acylations (entries 8-11), with methyl glutaricanhydride (3a) proving optimal. Using this electrophile the resolvedthiol could be isolated in 33% ee at 50% conversion (using either 1 or 5mol % of catalyst 13), corresponding to S=2.7.

Product esters 7a and 7b were both formed with excellentenantioselectivity (>90% ee) and with encouraging diastereocontrol(67:33 dr, entry 8). With respect to the anhydride, the desymmetrisationaspect of the reaction was highly selective—the parameter ee_(desymm)(Table 1) represents the percentage excess of products derived fromattack of the thiol 1 at one prochiral anhydride carbonyl moiety overthe other (i.e. the enantiomeric excess of the desymmetrised product ifthe combined thioester diastereomers were substituted by an achiral(non-hydroxide) nucleophile without racemisation). It is also noteworthythat in the presence of triethylamine as an achiral catalyst thediastereoselectivity is reversed, with 19 as the major diastereomer.

Next the steric and electronic characteristics of the catalyst weresystematically varied through the synthesis and evaluation ofsulfonamides 14-17. While the electron deficientpentafluorophenyl-substituted catalyst fared a little better than 13,less acidic analogues 15-17 respectively possessed enhanced selectivityprofiles (entries 12-15). Given the superiority of the hindered promoter16, it was decided to accentuate the steric bulk of the sulfonamidefurther via the synthesis of the novel catalyst 18, which proved almostas active as 13 yet promoted the acylation with a synthetically usefulKR selectivity of 8.5 (entry 16). Further optimisation of the reactionconditions (entries 17-19) resulted in the KR of thiol 1 withoutstanding selectivity (S=25.5)—allowing the isolation of resolved(R)-1 in 90% ee at 54% conversion, along with ester 7a (formed as themajor diastereomer, 89:11 dr) in 98% ee, with an excellent attendantee_(desymm) of 96% (entry 19).

TABLE 1 Kinetic resolution of thiol 1 with simultaneous desymmetrisationof achiral-anhydrides 3-5

anhydride catalyst T cony. ee_(esterA) ee_(esterB) ee_(desym) ee_(thiol)entry (equiv.) (mol %) solvent (° C.) (%)^(c) dr^(d) (%)^(e) (%)^(e)(%)^(e,f) (%)^(e) S^(g)  1 2a (0.5) 10 (5) MTBE rt 49 — 6.5 — —  7 1.2 2 2a (0.5) 11 (5) MTBE rt 50 — 9 — —  9 1.3  3 2a (0.5) 12 (5) MTBE rt50 — 6 — —  6 1.2  4 2a (0.5) 13 (5) MTBE rt 50 — 13 — — 13 1.5  5 2a(0.5) 13 (5) Et₂O rt 50 — 14 — — 14 1.5  6 2a (0.5) 13 (5) THF rt 39 —27 — — 17 2.1  7 2a (0.5) 13 (5) CH₂Cl₂ rt 16 — n.d. — — — —  8 3a (0.5)13 (5) MTBE rt 50 66.5:33.5 95 91 92 33 2.7  9 3a (0.5) 13 (1) MTBE rt49 67:33 97 88 94 33 2.7 10 4 (0.5) 13 (5) MTBE rt 50 n.d. n.d. n.d.n.d. 21 1.8 11 5 (0.5) 13 (5) MTBE rt 50 60:40 n.d. n.d. n.d. 26 2.3 123a (0.5) 14 (5) MTBE rt 49 70:30 97 87 94 41 3.9 13 3a (0.5) 15 (5) MTBErt 47 73:27 97 93 96 41 4.0 14 3a (0.5) 16 (5) MTBE rt 44 79:21 97 90 9645 5.6 15 3a (0.5) 17 (5) MTBE rt 48 75:25 95 84 92 44 4.3 16 3a (0.5)18 (5) MTBE rt 48 89:11 95 68 90 60 8.5 17^(a) 3a (0.5) 18 (5) MTBE  043 89:11 98 78 96 58 13.6 18^(a) 3a (0.75) 18 (10) MTBE  0 62 79:21 9590 94 93 11.6 19^(b) 3a (0.75) 18 (10) MTBE −30 54 89:11 98 84 96 9025.5 20^(b) 2b (0.75) 18 (10) MTBE −30 33 — n.d. — — 42 (85)^(h) 17.921^(b) 3b (0.75) 18 (10) MTBE −30  4 — n.d. — — n.d. n.d. 22^(b) 2a(0.75) 18 (10) MTBE −30 50 — n.d. — — 68 (68)^(h) 10.7 ^(a)48 h. ^(b)72h. ^(c)Conversion was determined using CSP-HPLC, where conversion = 100× ee_(thiol)/(ee_(thiol) + ee_(thioester)); the value of ee_(thioester)was calculated using all four thioester stereoisomers.^(d)Diastereomeric ratio = (6-9a + ent-6-9a):(6-9b + ent-6-9b).^(e)Determined by CSP-HPLC, see supporting information.^(f)Desymmetrisation efficiency: the enantiomeric excess of thedesymmetrised product if the combined thioester products weresubstituted by an achiral (non-hydroxide) nucleophile, calculated as 100× [(6-9a + 6-9b) − (ent-6-9a + ent-6-9b)]/[(6-9a + 6-9b) +(ent-6-9a +ent-6-9b)]. ^(g)S = enantioselectivity (k_(fast/kslow,)). ^(h)Value inparenthesis refers to the ee of the thiol obtained after deprotectionvia cleavage of the combined thioester products.

Thus, under optimum conditions 18 is capable of mediating the highlyefficient and selective KR of a substrate class previously outside theorbit of direct enantioselective catalytic acylation, with thesimultaneous desymmetrisation of a synthetically useful class ofinexpensive achiral anhydride acylating agent—also with excellentenantioselectivity. To demonstrate that the desymmetrisation and kineticresolution processes are synergistic, we next carried out the processunder optimum conditions using the non-prochiral anhydrides 2a, 2b and3b (entries 20-22). Kinetic resolution was either too slow or proceededwith lower enantioselectivity using these electrophiles.

Attention now turned to the question of substrate scope (Table 2). Itwas found that variation of the steric bulk of both the aromatic andaliphatic substituent is well tolerated by the catalyst—for example,α-Me, -Et, -^(i)Pr and -^(t)Bu derivatives of benzyl mercaptan (i.e. 1and 20-22, entries 1-4) could be resolved with excellent selectivity (upto S>50), resulting in the isolation of the unreacted thiol with >90% eeat ca. 50% conversion. A strong correlation between increasing aliphaticsubstituent bulk and selectivity was observed; however it is noteworthythat even the challenging substrate 20 (where the steric discrepancybetween the two carbon-based substituents is smallest) could be resolvedwith synthetically useful selectivity. Variation of the characteristicsof the aromatic substituent produced interesting results—substitution inthe para-position either slightly reduces or has no impact onenantioselectivity (23-25, entries 5-7), while steric bulk at theortho-position dramatically improved the KR; in optimum cases thisresulted in levels of enantiodiscrimination (S>>100) more usuallyassociated with the enzymatic KR of alcohols (26-28, entries 8-12).

Synthesis of Pregabalin [(R)-3-(aminomethyl)-5-methylhexanoic acid]

To demonstrate the potential utility of this methodology, the KR ofthiol 28 (0.80 mmol) was carried out with catalyst 18 in the presence ofachiral anhydride 4, which furnished (R)-28 (0.39 mmol, 99% ee) and thering-opened product 29 (0.40 mmol) with excellent efficiency at 51%conversion as shown in FIG. 1. Thioester 29 (as a mixture ofdiastereomers) was then treated with aqueous ammonia, resulting in itscleavage to afford the other thiol enantiomer (S)-28 (96% ee, 0.35 mmol)and the aminolysed product (S)-30 (97% ee, 0.38 mmol), again with highefficiency. Hemiamide (S)-30 is a precursor which can be converted in asingle step to the (R)-antipode of the anticonvulsive agent Pregabalinand thus this sequence—in addition to serving as a highly efficient KRof 28—constitutes a rapid and convenient formal synthesis of the‘blockbuster’ drug (marketed as ‘Lyrica’®).

TABLE 2 Evaluation of substrate scope

en- time conv. ee_(thiol) abs. try substrate X (h) (%)^(a) (%)^(b) S^(c)config.^(d) 1

  20 0.75 68 63 97 14.5 (R) 2

  21 0.75 74 56 91 19.0 (R) 3^(e)

  1 0.75 68 54 90 25.5 (R) 4^(f)

  22 0.75 96 52 94 51.5 (R) 5

  23 0.75 72 65 95 10.7 (R) 6

  24 0.90 120 56 87 15.0 (R) 7

  25 0.75 74 58 82 9.7 (R) 8^(g) 0.75 72 45 59 11.8 (R) 9^(h)

  26 0.75 96 51 90 36.6 (R) 10

  27 0.75 48 50 95 (94)^(j) 126.0 (R) 11

  28 0.75 48 50 98 (96)^(j) 265.0 (R) 12^(k) 0.75 48 43 75 (98)^(j)275.0 (R) ^(a)Refers to conversion, determined using CSP-HPLC, whereconversion = 100 × ee_(thiol)/(ee_(thiol) + ee_(thioester)).^(b)Determined by CSP-HPLC, see supporting information. ^(c)S =enantioselectivity (k_(fast/kslow,) see ref. 1). ^(d)Refers to theabsolute configuration of the recovered thiol product (see supportinginformation). ^(e)Data from Table 1. ^(f)A repeat of this experiment(conv. 52%, S = 50.4) resulted in the isolation of the unreacted(R)-thiol in 47% yield and 95% ee after chromatography. After aminolysisof the combined thioester products the (S)-thiol was obtained in 43%isolated yield and 86% ee. ^(g)Reaction at −40° C. ^(h)A repeat of thisexperiment in which the combined thioester diastereomers were aminolysedresulted in the isolation of the corresponding hemiamide in 93% ee.^(i)A repeat of this experiment (conv. 51%, S = 249.0) resulted in theisolation of the unreacted (R)-thiol in 48% yield and 99.6% ee afterchromatography. After aminolysis of the combined thioester products the(S)-thiol was obtained in 44% isolated yield and 95% ee. ^(j)Value inparenthesis refers to the ee of the thiol obtained after deprotectionvia cleavage of the combined thioester products. ^(k)Reaction at −45° C.

CONCLUSIONS

Disclosed herein is novel sulfonamide catalyst 18, which promotes thehighly enantioselective (S>10) direct acylative KR of a sec-thiols forthe first time, allowing their isolation in >90% ee at ca. 50%conversion. Under optimum conditions at low catalyst loadings theselectivity (k_(fast)/k_(slow)) of these processes is in the range of50-275, thus using the artificial catalyst 18 it is possible to achievelevels of enantiodiscrimination more usually associated with acylativeKR by biological catalysts, using a substrate class not hithertodemonstrated to be generally amenable to enzyme-mediated directacylative KR. In addition, the thiol-KR is accompanied by a synergistic,simultaneous desymmetrisation of an achiral anhydride electrophile—whichoccurs with excellent levels of enantioselectivity on a par with thoseassociated with the best anhydride desymmetrisation methodologies in theliterature. This catalytic desymmetrisation of an electrophile while itkinetically resolves a nucleophile is, to the best of our knowledge, ahitherto unreported phenomenon which possesses excellent potential as atool to considerably improve upon both the synthetic utility and atomeconomy of acylative KR processes.

Experimental General

Proton Nuclear Magnetic Resonance spectra were recorded on a 400 MHzspectrometer in CDCl₃ (to prevent oxidation of the thiols, CDCl₃ waspurified by distillation and stored under argon over molecular sieves)or DMSO-d₆ and referenced relative to residual CHCl₃ (δ=7.26 ppm) orDMSO (δ=2.54 ppm). Chemical shifts are reported in ppm and couplingconstants in Hertz. Carbon NMR spectra were recorded on the sameinstrument (100 MHz) with total proton decoupling. All melting pointsare uncorrected. Flash chromatography was carried out using silica gel,particle size 0.04-0.063 mm. TLC analysis was performed on precoated60F₂₅₄ slides, and visualised by UV irradiation and KMnO₄ staining.Optical rotation measurements are quoted in units of 10⁻¹ deg cm² g⁻¹.Toluene and methylene chloride were distilled over calcium hydride andstored under argon. Tetrahydrofuran and diethyl ether were distilledover sodium-benzophenone ketyl radical and stored under argon.Commercially available anhydrous t-butyl methyl ether was used. Allreactions were carried out under a protective argon atmosphere.Analytical CSP-HPLC was performed on a Daicel CHIRALPAK AS, AD, orChiralcel OD-H (4.6 mm×25 cm) columns. The absolute configuration ofeach enantioenriched thiol was determined after derivatisation with(R)-2-methoxy-2-phenylacetic acid and analysis of the correspondingthioester by ¹H NMR spectroscopy as recently reported in the literature.In the cases of thiols 20 and 25, the absolute configuration (andfidelity of the literature ¹H NMR spectroscopic method) could be alsoconfirmed by comparison of the optical rotation with the literaturedata.

Synthesis of Secondary Thiols

All secondary thiols were obtained from the corresponding thioester byreaction with LiAlH₄ in anhydrous THF. Thioesters 20, 21, 23, 24 and 27were made from the corresponding alcohols via a modification of theMitsunobu protocol. Thioesters 1, 22, 25, 26 and 28 were obtained fromthe corresponding alcohols via a two step procedure involving initialactivation of the hydroxyl function by conversion to the correspondingmesylate (1, 25, 26 and 28) or bromide (22) followed by displacementwith the potassium salt of thioacetic acid in acetone or DMF.

General Procedure for the Preparation of Thioesters Via the MitsunobuProtocol

Diisopropyl azodicarboxylate (DEAD) (2.95 mL, 15.0 mmol) was addeddropwise and via syringe to an ice-cooled solution of triphenylphosphine(3.93 g, 15.0 mmol) in dry THF (30 mL) under argon. After 1 h, asolution of the appropriate alcohol (7.50 mmol) and thioacetic acid(1.07 mL, 15.0 mmol) in THF (10 mL) was slowly injected and the mixturewas stirred continuously while warming to room temperature. After 12 h,the solvent was evaporated in vacuo and the resulting yellow slurry wassuspended in n-hexane (40 mL) and stirred for 2 h. After removal of theprecipitate that had formed by filtration, the filtrate was concentratedin vacuo and the desired product obtained as colourless oil afterpurification by flash chromatography on silica gel.

1-Phenylethyl thioacetate

Following the general procedure outlined above, the product was isolatedin 75% yield as a colourless oil.

TLC (Hexane:AcOEt, 96:4 v/v): R_(f)=0.40. ¹H NMR (400 MHz, CDCl₃): δ7.40-7.23 (m, 5H), 4.77 (q, J=7.0 Hz, 1H), 2.33 (s, 3H), 1.68 (d, J=7.0Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 194.6 (q), 142.1 (q), 128.1, 126.9,126.7, 42.5, 30.0, 21.7.

Thioacetic acid S-[1-(4-methoxy-phenyl)-ethyl]ester

Following the general procedure outlined above, the product was isolatedin 58% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.30. ¹H NMR (400 MHz, CDCl₃): δ7.28 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.74 (q, J=7.0 Hz, 1H),3.82 (s, 3H), 2.32 (s, 3H), 1.67 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz,CDCl₃): δ 195.3 (q), 158.7 (q), 134.6 (q), 128.3, 113.9, 55.3, 42.5,30.5, 22.3. HRMS (m/z): [M+H]⁺ calcd. for C₁₁H₁₅O₂S 211.0793. found,211.0797.

Thioacetic acid S-[1-(4-chloro-phenyl)-ethyl]ester

Following the general procedure outlined above, the product was isolatedin 90% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.37. ¹H NMR (400 MHz, CDCl₃): δ7.30 (m, 4H), 4.73 (q, J=7.3 Hz, 1H), 2.32 (s, 3H), 1.65 (d, J=7.3 Hz,3H). ¹³C NMR (100 MHz, CDCl₃): δ 194.4 (q), 140.9 (q), 132.5 (q), 128.2,128.1, 41.8, 30.0, 21.5. HRMS (m/z): [M+H]⁺ calcd. for C₁₀H₁₂OSCl215.0297. found, 215.0301.

Thioacetic acid S-(1-o-tolyl-ethyl) ester

Following the general procedure outlined above, the product was isolatedin 76% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.34. ¹H NMR (400 MHz, CDCl₃): δ7.34 (d, J=7.0 Hz, 1H), 7.25-7.15 (m, 3H), 4.95 (q, J=7.0 Hz, 1H), 2.41(s, 3H), 2.34 (s, 3H), 1.68 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃):δ 195.0 (q), 139.4 (q), 135.1 (q), 130.1, 126.8, 126.2, 125.8, 38.9,29.9, 21.6, 18.8. HRMS (m/z): [M+Na]⁺ calcd. for C₁₁H₁₄ONaS 217.0663.found, 217.0668.

Thioacetic acid S-(1-phenyl-propyl) ester

Following the general procedure outlined above, the product was isolatedin 73% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 1:1 v/v): R_(f)=0.51. ¹H NMR (400 MHz, CDCl₃): δ7.38-7.23 (m, 5H), 4.51 (t, J=7.5 Hz, 1H), 2.32 (s, 3H), 2.04-1.92 (m,2H), 0.93 (t, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 194.5 (q),141.3 (q), 128.1, 127.2, 126.8, 49.2, 30.1, 28.9, 11.7. HRMS (m/z):[M+Na]⁺ calcd. for C₁₁H₁₄ONaS 217.0663. found, 217.0665.

General Procedure for the Preparation of Thioesters Via the MesylateIntermediate

Triethylamine (TEA) (1.25 mL, 9.00 mmol) was added via syringe to asolution of the appropriate alcohol (7.50 mmol) in dry CH₂Cl₂ (30 mL)under an argon atmosphere. The mixture was cooled to 0° C. andmethanesulfonyl chloride (640 μL, 8.25 mmol) was added dropwise. Thereaction was stirred continuously while it warmed to room temperature.After 12 h, the mixture was poured into an aqueous solution of HCl (1 N,30 mL), the resulting mixture was then transferred to a separatingfunnel and the organic and aqueous layers were separated. The aqueouslayer was extracted with CH₂Cl₂ (2×30 mL) and the combined organiclayers were washed with HCl (1 N) (30 mL) and a saturated aqueoussolution of NaHCO₃ (30 mL). The organic phase was then dried overmagnesium sulphate, filtered and evaporated to afford the desiredintermediate as a colourless oil. This was immediately dissolved in dryacetone (10 mL) and potassium thioacetate (1.71 g, 15.0 mmol) was added.The reaction was then heated to reflux until none of the mesylateintermediate could be detected by ¹H-NMR spectroscopic analysis (12-28h). The mixture was then filtered, the filtrate evaporated and the crudepurified by flash-chromatography.

Thioacetic acid (2-methyl-1-phenyl-propyl) ester

Following the general procedure outlined above, the product was isolatedin 74% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.42. NMR (400 MHz, CDCl₃): δ7.22-7.35 (m, 5H), 4.44 (d, J=8.0 Hz, 1H), 2.32 (s, 3H), 2.08-2.22 (m,1H), 1.06 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.5 Hz, 3H). ¹³C NMR (100 MHz,CDCl₃): δ 194.2 (q), 141.2 (q), 127.8, 127.7, 126.5, 54.8, 33.1, 30.2,20.3, 20.1. HRMS (m/z): [M+Na]⁺ calcd. for C₁₂H₁₆ONaS 231.0820. found,231.0819.

Thioacetic acid S-(1-naphthalen-1-yl-ethyl) ester

Following the general procedure, the product was isolated in 69% yieldas a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.34. ¹H NMR (400 MHz, CDCl₃): δ8.09 (d, J=8.5 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H),7.61-7.43 (m, 4H), 5.56 (q, J=7.0 Hz, 1H), 2.37 (s, 3H), 1.87 (d, J=7.0Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 195.1 (q), 136.8 (q), 133.5 (q),130.1 (q), 128.5, 127.8, 125.9, 125.4, 124.8, 124.1, 122.7, 38.2, 29.9,21.8. HRMS (m/z): [M+Na]⁺ calcd. for C₁₄H₁₄ONaS 253.0663. found,253.0659.

Thioacetic acid S-(1-naphthalen-2-yl-ethyl) ester

Following the general procedure outlined above, the product was isolatedin 62% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.31. ¹H NMR (400 MHz, CDCl₃): δ7.88-7.80 (m, 4H), 7.54-7.44 (m, 3H), 4.95 (q, J=7.0 Hz, 1H), 2.34 (s,3H), 1.78 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 194.6 (q),139.4 (q), 132.8 (q), 132.2 (q), 128.0, 127.4, 127.1, 125.8, 125.5,125.2, 125.1, 42.6, 30.0, 21.6. HRMS (m/z): [M+H]⁺ calcd. for C₁₄H₁₅ONS231.0844. found, 231.0848.

Thioacetic acid 1-(2,4,6-trimethyl-phenyl)-ethyl ester

Following the general procedure outlined above, the product was isolatedin 62% yield as a colourless oil.

TLC (Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.40. ¹H NMR (400 MHz, CDCl₃): δ6.85 (s, 2H), 5.35 (q, J=7.5 Hz, 1H), 2.44 (s, 6H), 2.33 (s, 3H), 2.26(s, 3H), 1.67 (d, J=7.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): 195.0 (q),136.3 (q), 136.1 (q), 135.4 (q), 135.2 (q), 130.3, 128.7, 37.4, 29.9,21.0, 20.7, 20.5, 20.3 Note: this compound exhibits NMR spectraconsistent with restricted rotation which is fast on the ¹H NMRspectroscopic time scale but slow on the ¹³C NMR spectroscopic timescale. HRMS (m/z): [M+Na]⁺ calcd. for C₁₃H₁₈ONaS 245.0976. found,245.0974.

Thioacetic acid S-(2,2-dimethyl-1-phenyl-propyl) ester

(1-Bromo-2,2-dimethyl-propyl)-benzene (1.00 g, 4.40 mmol) was dissolvedin dry DMF (5 mL) under an argon atmosphere. Potassium thioacetate (2.51g, 22.0 mmol) was added and the reaction was heated to 50° C. for 7days. The solution was then concentrated and the product purified bycolumn chromatography to obtain the desired thioester (970 mg, 99%). TLC(Hexane:CH₂Cl₂, 7:3 v/v): R_(f)=0.40. ¹H NMR (400 MHz, CDCl₃): δ7.33-7.22 (m, 5H), 4.52 (s, 1H), 2.32 (s, 3H), 1.00 (s, 9H). ¹³C NMR(100 MHz, CDCl₃): δ 193.9 (q), 140.4 (q), 129.0, 127.2, 126.4, 58.7,34.9 (q), 30.2, 27.6. HRMS (m/z): [M+Na]⁺ calcd. for C₁₃H₁₈ONaS245.0976. found, 245.0972.

General Procedure for the Reduction of Thioesters to Thiols

A 100 mL three neck round-bottomed flask, flame dried and equipped witha reflux condenser, was charged with dry THF (15 mL) and LiAlH₄ (114 mg,3.0 mmol). The suspension was cooled to 0° C. and a solution of theappropriate thioester (3.0 mmol) in dry THF (5 mL) was added in adropwise manner. After 1 h refluxing, the reaction mixture was cooled to0° C. and carefully quenched with aqueous HCl (1 M) (10 mL). The organiclayer was separated and the aqueous solution extracted with Et₂O (2×15mL). The combined organic layers were then dried over magnesiumsulphate, filtered and evaporated and the desired product obtained inexcellent yield after purification by flash-chromatography on silicagel.

Synthesis of catalyst18—2,4,6-Triisopropyl-N-[(6-methoxy-quinolinyl)-(5-vinyl-1-azabicyclo[2.2.2.]octyl)-methyl]benzenesulfonamide

To a suspension of 9-epi-QA.3HCl (1.0 g, 2.31 mmol) in dry CH₂Cl₂ (20mL), triethylamine (1.5 mL, 10.4 mmol) was then added via syringe andthe resulting clear solution was cooled to 0° C. A solution of2,4,6-Triisopropyl-phenyl sulphonyl chloride (700 mg, 2.31 mmol) inCH₂Cl₂ (5 mL) was then slowly injected and the mixture was allowed towarm to room temperature and stirred for 15 h. After evaporation of thesolvent, the crude residue was purified by flash chromatographyaffording the desired sulphonamide catalyst 18 (1.10 g, 81%). M.p.115-118° C.; TLC (Hexane:EtOAc, 1:1 v/v): R_(f)=0.48. [α]²⁰ ₅₈₉=−43.0(c=0.50, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆ only the major rotamerquoted): δ 8.52 (d, 1H, J=4.4 Hz), 7.92 (d, 1H, J=9.7 Hz), 7.47-7.41 (m,2H), 7.40 (d, 1H, J=4.4 Hz), 6.99 (s, 2H), 5.73-5.70 (m, 1H), 5.16 (d,1H, J=10.4 Hz), 4.96 (d, 1H, J=17.3 Hz), 4.89 (d, 1H, J=10.6 Hz), 3.96(s, 3H, OCH₃), 3.83-3.94 (m, 3H), 3.07-3.09 (m, 1H), 2.81-2.93 (m, 3H),2.63-2.68 (m, 1H), 2.46-2.48 (m, 1H), 2.21 (bs, 1H), 1.42-1.58 (m, 3H),1.13-1.16 (m, 12H), 0.87 (d, 6H, J=6.5 Hz), 0.71-0.78 (m, 1H). ¹³C NMR(100 MHz, DMSO-d₆): δ 157.7, 152.1, 149.2, 147.8, 144.8, 144.1, 142.2,134.6, 131.9, 127.9, 123.3, 121.2, 120.8, 114.7, 102.2, 60.7, 56.0,55.3, 52.3, 40.3, 39.3, 33.7, 29.6, 27.8, 27.4, 25.4, 25.2, 24.6, 23.8.IR (neat): 3658, 2981, 2889, 1473, 1462, 1382, 1252, 1150, 1072, 954cm⁻¹. HRMS (m/z): [M+H]⁺ calcd. for C₃₅H₄₈N₃O₃S 590.3416. found,590.3410.

Catalyst Evaluation at Low Temperature (General Procedure A)

A 20 mL reaction vial containing a stirring bar was charged with3-methylglutaric anhydride (3a) (28.8 mg, 0.225 mmol) and 18 (17.7 mg,0.030 mmol). The reaction vial was flushed with argon and fitted with aseptum. MTBE (degassed) was then injected (1.5 mL, 0.2M) and thesolution cooled to −30° C. The relevant thiol (0.30 mmol) was added viasyringe and the resulting solution was stirred for the time indicated inTable 2. Conversion to the product was then monitored by ¹H-NMRspectroscopic analysis and the mixture was purified byflash-chromatography in order to separate the unreacted thiol from thethioester product.

Enantiomeric Excess, Conversion and S Factor Determination Procedures(Table 2)

The enantiomeric excess of each unreacted thiol was determined byCSP-HPLC after conversion to the corresponding Michael adduct withacrylonitrile. The enantiomeric excess of each ‘fast reacting’ thiol wasdetermined by CSP-HPLC after aminolysis of the thioester product andderivatisation of the thiol to the corresponding Michael adduct withacrylonitrile. Conversion was determined using CSP-HPLC, whereconversion=100×ee_(thiol)/(ee_(thiol)+ee_(thioester)) and theSelectivity Factor (S) was calculated according to the method developedby Kagan (Kagan, H. B. & Fiaud, J. C. Kinetic resolution. Top.Stereochem. 18, 249-330 (1988)).

Thiol Derivatisation (General Procedure B)

The appropriate ‘slow reacting’ thiol (as obtained afterflash-chromatography of the crude reaction mixture) was dissolved inCH₂Cl₂ (1.0 mL) under an argon atmosphere. Triethylamine (5.0 eq.) andacrylonitrile (10.0 eq.) were added and the mixture was stirred at roomtemperature for 3 h. After removal of the volatiles under reducedpressure, the crude product was then purified by flash-chromatography toafford the desired Michael adduct in quantitative yield.

One-Pot Thioester Aminolysis and Thiol Derivatisation (General ProcedureC)

The appropriate thioester (as obtained after flash-chromatography of thereaction crude) was dissolved in CH₂Cl₂ (3.0 mL). Acrylonitrile (10.0eq.) and ammonia (35% aqueous solution, 3.0 mL) were added and thebiphasic mixture was vigorously stirred at room temperature for 3 h. Thereaction was then diluted with CH₂Cl₂ (10.0 mL) and H₂O (10.0 mL) andtransferred to a separating funnel. The organic and aqueous layers wereseparated and the organic layer was dried over MgSO₄, filtered andevaporated under reducer pressure. The desired Michael addition productwas obtained in quantitative yield after purification byflash-chromatography.

Thioester Derivatisation as the Corresponding o-Nitrophenyl Ester (Table1)

Enantioselectivity data in Table 2 were obtained by recovering theunreacted thiol and separating it from the thioester products, whichwere then aminolysed to the other thiol antipode and analysed separatelyby CSP-HPLC. In Table 1 however, enantioselectivity data were availablefrom analysis of the thioester diastereomers, which were readilyseparable by CSP-HPLC after conversion to the correspondingo-nitrophenylester derivatives via the procedure outlined below.

A 5 mL reaction vial containing a stirring bar was charged with thethioester (as obtained after flash-chromatography of the reactioncrude), o-nitrophenol (2.0 eq.), DMAP (0.1 eq.), DCC (1.2 eq.) andCH₂Cl₂ (0.05 M). The reaction vial was flushed with argon, fitted with aseptum and stirred at room temperature for 12 h. The mixture was thenfiltered and the resulting clear solution was then purified byflash-chromatography.

Characterisation Data

Where indicated the absolute configuration of the thiols was establishedby following the literature procedure of Porto, S., Seco, J. M., Ortiz,A., Quiñoá, E. & Riguera, R. Chiral thiols: the assignment of theirabsolute configuration by ¹H NMR. Org. Lett. 24, 5015-5018 (2007).

3-Methyl-4-(2-methyl-1-phenyl-propylsulfanylcarbonyl)-butyric acid(Table 1, entry 19)

TLC (n-Hexane:EtOAc, 97:3, v/v): R_(f)=0.38. ¹H NMR (400 MHz, CDCl₃): δ7.31-7.20 (m, 5H), 4.43 (d, J=8.0 Hz, 1H), 2.66-2.36 (m, 4H), 2.26-2.20(m, 1H), 2.18-2.06 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.98 (d, J=6.5 Hz,3H), 0.86 (d, J=6.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 197.0, 176.6,141.5, 128.3, 128.2, 127.0, 55.2, 50.0, 40.0, 33.6, 27.9, 20.7, 20.5,19.5; IR (neat): 2965, 2931, 1704, 1685, 1450, 1007, 911, 727, 697 cm⁻¹.HRMS (m/z): [M+Na]⁺ calcd. for C₁₆H₂₂O₃NaS 317.1187. found, 317.1198.Note: Major diastereomer is 7a

2-Methyl-1-phenyl-propane-1-thiol ((R)-1, table 1, entry 19)

After 68 h, the enantioenriched unreacted thiol was recovered in 90.4%ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 12.3 min (minorenantiomer) and 14.0 min (major enantiomer).

Conversion=53.5%; S Factor=25.5.

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.52. [α]²⁰ _(D)=+99.0 (c=0.54,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.36-7.20 (m, 5H), 3.78 (dd, J=8.5and 5.0 Hz, 1H), 2.20-2.05 (m, 1H), 1.83 (d, J=5.0 Hz, 1H), 1.12 (d,J=6.5 Hz, 3H), 0.85 (d, J=6.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 143.8(q), 127.9, 127.0, 126.5, 51.5, 35.4, 20.4, 20.3. HRMS (m/z): [M]⁺calcd. for C₁₀H₁₄S 166.0816. found, 166.0810.

The absolute configuration of 1 was established following the literatureprocedure.

1-Phenylethanethiol ((R)-20, Table 2, entry 1)

After 68 h, the enantioenriched unreacted (R)-thiol was recovered in97.1% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 14.6 min (minorenantiomer) and 16.1 min (major enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.49. [α]²⁰ _(D)=+62.0 (c=0.38,EtOH); Lit. [α]²⁵ _(D)=−88.7 (c=0.63, EtOH; 99% ee, (S)-enantiomer)³. ¹HNMR (400 MHz, CDCl₃): δ 7.42-7.23 (m, 5H), 4.26 (app quintet, J=6.5 Hz,1H), 2.02 (d, J=5.0 Hz, 1H), 1.70 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz,CDCl₃): δ 145.4 (q), 128.2, 126.7, 125.9, 38.3, 25.6. HRMS (m/z): [M+H]⁺calcd. for C₈H₁₁S 139.058. found, 139.0585.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in57.4% ee. Conversion=62.8%; S Factor=14.5.

The absolute configuration of 20 was established following the procedurereported in the literature and (with agreement) by comparing the opticalrotation with the literature data.

1-Phenyl-propane-1-thiol ((R)-21, Table 2, entry 2)

After 74 h, the enantioenriched unreacted (R)-thiol was recovered in91.2% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 11.4 min (minorenantiomer) and 13.2 min (major enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.45. [α]²⁰ _(D)=+70.2 (c=0.45,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.38-7.22 (m, 5H), 3.92 (dt, J=7.5and 5.0 Hz, 1H), 2.07-1.90 (m, 3H), 0.96 (t, J=7.5 Hz, 3H). ¹³C NMR (100MHz, CDCl₃): δ 144.1 (q), 128.1, 126.7, 126.5, 45.5, 32.4, 12.1. HRMS(m/z): [M]⁺ calcd. for C₉H₁₂S 152.0660. found, 152.0653.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in72.0% ee. Conversion=55.9%; S Factor=19.0.

The absolute configuration of 21 was established following the procedurereported in the literature.

2,2-Dimethyl-1-phenyl-propane-1-thiol ((R)-22, Table 2, entry 4)

After 96 h, the enantioenriched unreacted (R)-thiol was recovered in93.8% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 9.5 min (majorenantiomer) and 11.7 min (minor enantiomer).

TLC (Hexane 100%): R_(f)=0.36. [α]²⁰ _(D)=+105.4 (c=0.51, CHCl₃). ¹H NMR(400 MHz, CDCl₃): δ 7.38-7.20 (m, 5H). 3.99 (d, J=5.0 Hz, 1H), 1.77 (d,J=5.0 Hz, 1H), 1.03 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 142.3 (q),128.4, 127.2, 126.5, 55.4 (q), 35.1, 27.2. HRMS (m/z): [M]⁺ calcd. forC₁₁H₁₆S 180.0973. found, 180.0975.

After hydrolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in87.2% ee. Conversion=51.8%; S Factor=51.5. The absolute configuration of22 was established following the procedure reported in the literature. Arepeat of this experiment (cony. 52%, S=50.4) resulted in the isolationof the unreacted (R)-thiol in 47% yield and 94.8% ee. After aminolysisof the combined thioester products the (S)-thiol was obtained in 43%isolated yield and 86.26% ee.

1-(4-Chloro-phenyl)-ethanethiol ((R)-23, Table 2, entry 5)

After 72 h, the enantioenriched unreacted (R)-thiol was recovered in95.3% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak AS (4.6 mm×25 cm), hexane/IPA: 96/4, 1.0 mLmin⁻¹, RT, UV detection at 220 nm, retention times: 17.1 min (majorenantiomer) and 18.7 min (minor enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.52. [α]²⁰ _(D)=+73.7 (c=0.36,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.32 (br s, 4H), 4.23 (dq, J=7.0 and5.0 Hz, 1H), 2.01 (d, J=5.0 Hz), 1.67 (d, J=7.0 Hz, 3H); ¹³C NMR (100MHz, CDCl₃): δ 143.9 (q), 132.3 (q), 128.4, 127.3, 37.6, 25.5. HRMS(m/z): [M+H]⁺ calcd. for C₈H₁₀SCl 173.0192. found, 173.0191.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in51.0% ee. Conversion=65.1%; S Factor=10.7. The absolute configuration of23 was established following the procedure reported in the literature.

1-(4-Methoxy-phenyl)-ethanethiol ((R)-24, Table 2, entry 6)

After 5 d, the enantioenriched unreacted (R)-thiol was recovered in87.1% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 98/2, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 22.3 min (minorenantiomer) and 24.1 min (major enantiomer).

TLC (Hexane:CH₂Cl₂, 8:2, v/v): R_(f)=0.35. [α]²⁰ _(D)=+47.3 (c=0.30,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.32 (d, J=8.5 Hz, 2H), 6.88 (d,J=8.5 Hz, 2H), 4.25 (dq, J=7.0 and 5.0 Hz, 1H), 3.82 (s, 3H), 2.00 (d,J=5.0 Hz), 1.67 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 158.6(q), 137.9 (q), 127.4, 113.9, 55.3, 38.2, 26.3. HRMS (m/z): [M+H]⁺calcd. for C₉H₁₃OS 169.0687. found, 169.0683.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in68.8% ee. Conversion=55.8%; S Factor=15.0. The absolute configuration of24 was established following the procedure reported in the literature.

1-Naphthalen-2-yl-ethanethiol ((R)-25, Table 2, entry 7)

After 74 h, the enantioenriched unreacted thiol was recovered in 82.0%ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 18.2 min (minorenantiomer) and 23.7 min (major enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.47. [α]²⁰ _(D)=+53.7 (c=0.38,CH₂Cl₂); Lit [α]²⁰ _(D)=+65.9 (c=0.58, CH₂Cl₂; 99% ee, (R)-enantiomer).¹H NMR (400 MHz, CDCl₃): δ 7.89-7.82 (m, 3H), 7.91-7.78 (m, 1H), 7.58(dd, J=8.5 and 1.8 Hz, 1H), 7.54-7.47 (m, 2H), 4.44 (dq, J=7.0 and 5.0Hz, 1H), 2.08 (d, J=5.0 Hz, 1H), 1.80 (d, J=7.0 Hz, 3H). ¹³C NMR (100MHz, CDCl₃): δ 143.2 (q), 133.3 (q), 132.6 (q), 128.5, 127.8, 127.7,126.2, 125.9, 125.0, 124.4, 39.0, 25.9. HRMS (m/z): [M+H]⁺ calcd. forC₁₂H₁₃S 189.0738. found, 189.0736.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in59.5% ee. Conversion=57.9%; S Factor=9.7. The absolute configuration of25 was established following the procedure reported in the literatureand (with agreement) by comparing the optical rotation with theliterature data.

1-Naphthalen-1-yl-ethanethiol ((R)-26, Table 2, entry 8)

After 96 h, the enantioenriched unreacted (R)-thiol was recovered in89.8% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 22.4 min (minorenantiomer) and 28.1 min (major enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.39. [α]²⁰ _(D)=−188.0 (c=0.40,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, J=8.5 Hz, 1H), 7.90 (d,J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 7.60 (t,J=7.0 Hz, 1H), 7.56-7.46 (m, 2H), 5.12-5.02 (m, 1H), 2.16 (d, J=5.0 Hz,1H), 1.90 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 140.6 (q),133.5 (q), 129.9 (q), 128.6, 127.3, 125.8, 125.2, 125.1, 122.5, 122.2,33.2, 24.7. HRMS (m/z): [M+H]⁺ calcd. for C₁₂H₁₃S 189.0738. found,189.0736.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in84.7% ee. Conversion=51.5; S Factor=36.6. The absolute configuration of26 was established following the procedure reported in the literature.

In a repeat of this experiment the combined hemithioester products (70.0mg, 0.22 mmol) were dissolved in CH₂Cl₂ (2 mL) and treated with aq. NH₃(2 mL). After stirring at room temperature for 4 h, the reaction wasthen diluted with CH₂Cl₂ (10.0 mL) and H₂O (5.0 mL) and transferred to aseparating funnel. The organic and aqueous layers were separated and theaqueous layer was washed with CH₂Cl₂ (2×10.0 mL). The aqueous layer wasthen acidified by addition of HCl (2 N) until pH=2.8 and evaporatedunder reduced pressure. After dissolving the mixture of product andsalts in the minimum amount of H₂O, the product was extracted with EtOAc(7×10 mL). The combined organic phases were then dried over magnesiumsulphate and the solvent was removed under reduced pressure to affordthe desired hemiamide as a white solid in 82% yield. (26.0 mg, 0.18mmol). 93.0% ee as determined by CSP-HPLC after transformation to thecorresponding o-nitrophenoxy ester, as per the procedure reported below.

¹H NMR (400 MHz, DMSO-d₆): δ 7.29 (s, 1H), 6.77 (s, 1H), 2.31-2.15 (m,2H), 2.11-1.88 (m, 3H), 0.88 (d, J=6.3 Hz, 3H). ¹³C NMR (100 MHz,DMSO-d₆): δ 173.7 (q), 173.2 (q), 41.8, 40.6, 27.2, 19.4. HRMS (m/z):[M+Na]⁺ calcd. for C₆H₁₁NO₃Na 168.0637. found, 168.0643.

The enantiomeric excess of the hemiamide was determined by CSP-HPLCafter conversion to the corresponding o-nitrophenyl ester.

A 5 mL reaction vial containing a stirring bar was charged with thehemiamide (20 mg, 0.137 mmol) and DCC (42.6 mg, 0.206 mmol).2-nitrophenol (27.8 mg, 0.20 mmol). The vial was flushed with argon anddry THF (0.5 mL) was added. After 10 min, a solution of 2-nitrophenol(28.6 mg, 0.206 mmol) in dry THF (0.5 mL) was then added via syringe andthe reaction mixture was stirred for 12 h at room temperature. Afterfiltration of the resulting white precipitate, the filtrate wasconcentrated in vacuo and the residue purified by chromatography onsilica gel to afford the desired compound in 30% yield (11.0 mg). 93.0%ee as determined by CSP-HPLC analysis (chromatogram below). ChiralpakOD-H (4.6 mm×25 cm), hexane/IPA: 90/10, 1.0 mL min⁻¹, RT, UV detectionat 220 nm, retention times: 48.2 min (minor enantiomer) and 56.5 (majorenantiomer).

1-o-Tolyl-ethanethiol ((R)-27, Table 2, entry 9)

After 48 h, the enantioenriched unreacted (R)-thiol was recovered in95.3% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0mL min⁻¹, RT, UV detection at 220 nm, retention times: 11.4 min (minorenantiomer) and 13.7 min (major enantiomer).

TLC (Hexane 100%): R_(f)=0.37. [α]²⁰ ₅₈₉=−17.4 (c=0.42, CHCl₃). ¹H NMR(400 MHz, CDCl₃): δ 7.50 (d, J=7.5 Hz, 1H), 7.28-7.21 (m, 1H), 7.20-7.13(m, 2H), 4.44 (dq, J=7.0 and 6.0 Hz, 1H), 2.43 (s, 3H), 1.93 (d, J=6.0Hz, 1H), 1.72 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 143.0 (q),134.2 (q), 130.0, 126.4, 126.1, 124.7, 33.8, 25.0, 18.8. HRMS (m/z):[M]⁺ calcd. for C₉H₁₂S 152.0660. found, 152.0661.

After aminolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in94.2% ee. Conversion=50.3%; S Factor=126.0.

The absolute configuration of 27 was established following the procedurereported in the literature.

1-(2,4,6-Trimethyl-phenyl)-ethanethiol ((R)-28, Table 2, entry 10)

After 48 h, the enantioenriched unreacted (R)-thiol was recovered in98.1% ee as determined by CSP-HPLC after conversion to the correspondingMichael addition adduct following the general procedure B.

CSP-HPLC analysis. Chiralpak AS (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0 mLmin⁻¹, RT, UV detection at 220 nm, retention times: 6.9 min (majorenantiomer) and 8.2 min (minor enantiomer).

TLC (Hexane:CH₂Cl₂, 9:1 v/v): R_(f)=0.44. [α]²⁰ ₅₈₉=+102.6 (c=0.35,CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 6.84 (s, 2H). 4.81 (dq, J=7.5 and 5.5Hz, 1H), 2.57 (br s, 3H), 2.38 (br s, 3H), 2.26 (s, 3H) 2.20 (d, J=5.5Hz, 1H), 1.73 (d, J=7.5 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 137.3,136.4 (q), 135.8, 134.3 (q), 131.0 (q), 128.7 (q), 32.8, 23.1, 20.6,20.2. HRMS (m/z): [M]⁺ calcd. for C₁₁H₁₆S 180.0973. found, 180.0978.

After hydrolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in96.4% ee. Conversion=50.4%; S Factor=265.0.

The absolute configuration of 28 was established following the procedurereported in the literature.

A repeat of this experiment (cony. 51%, S=249) resulted in the isolationof the unreacted (R)-thiol in 48% yield and 99.6% ee. After aminolysisof the combined thioester products the (S)-thiol was obtained in 44%isolated yield and 94.7% ee.

A repeat of this experiment at −45° C. resulted in the isolation of the(R)-thiol in 75.4% ee as determined by CSP-HPLC after conversion to thecorresponding Michael addition adduct following the general procedure B.

After hydrolysis of the thioester product and derivatisation as pergeneral procedure C, the reacted enantioenriched thiol was recovered in98.3% ee. Conversion=43.4%; S Factor=275.0.

HPLC Calculation Methods3-Methyl-4-(2-methyl-1-phenyl-propylsulfanylcarbonyl)-butyric acid

Chiralpak OD-H (4.6 mm×25 cm), hexane/IPA: 95/5, 1.0 mL min⁻¹, RT, UVdetection at 220 nm

Chromatogram of the thioesters 7a-b (derivatised as their o-nitrophenylesters for analysis via CSP-HPLC) from the reaction of 1 with 3 in thepresence of triethylamine and an achiral thiourea as catalysts. Thechromatogram clearly identifies the enantiomeric relationship betweenthe peaks at 16.2 and 23.1 min (7a and its enantiomer) and between thoseat 17.9 min and 48.0 min (7b and its enantiomer).

Peak No Result Ret. Time (min) 1 19.870 16.199 2 8.148 17.894 3 19.78023.066 4 7.983 48.045

Chromatogram of the thioesters 7a-b (derivatised as their o-nitrophenylesters for analysis via CSP-HPLC) from the reaction of (S)-1 (84.5% ee)with 3 in the presence of triethylamine and an achiral thiourea ascatalysts. The chromatogram clearly allows the identification of themajor diastereomer 7a derived from attack of the enantioenriched thiolon a single prochiral carbonyl group to give (R)-stereochemistry at thecarbon chain. This is the sense of stereoinduction expected fromprevious work and confirmed by conversion of a mixture of thioesterdiastereomers derived from the addition of 22 to 3 catalysed by 18 to alactone of known configuration (see below). The 84.5% ee relationshipbetween the peaks at 17 and 48 min confirms the identity of ent-7a.Likewise, the larger of the two peaks associated with the 7bdiastereomer must therefore be ent-7b (i.e. with (S)-stereochemistry atthe carbon bound to the sulphur atom).

Peak No Result Ret. Time (min) 1 19.603 14.618 2 13.613 16.034 3 2.37520.309 4 0.846 42.152Determination of the Sense of Stereoinduction Associated with theDesymmetrisation Reaction

The sense of stereoinduction associated with the desymmetrisationreaction was determined by conversion of the mixture of thioesterdiastereomers derived from the addition of 22 to 3 (i.e. Table 2, entry4) to the lactone shown below and comparison of the optical rotation ofthat lactone derivative with the literature data (Irwin, A. J. & Jones,J. B. Asymmetric syntheses via enantiotopically selective horse liveralcohol dehydrogenase catalyzed oxidations of diols containing aprochiral center. J. Am. Chem. Soc. 99, 556-561 (1977)).

The mixture of thioester diastereomers (92.5 mg, 0.30 mmol) wasdissolved in THF (5 mL) and LiOH (12.6 mg, 0.30 mmol) was added. Thereaction was heated to 50° C. and stirred for 15 minutes. LiClO₄ (159.6mg, 1.50 mmol) and NaBH₄ (56.7 mg, 1.50 mmol) were then added and thereaction mixture was stirred at 50° C. for 1 h. The solvent wasconcentrated in vacuo, HCl (10 N, 5 mL) was added and the mixture wasstirred at room temperature for 3 h. The desired product was extractedwith CHCl₃ (3×10 mL), the combined extracts were dried (MgSO₄),concentrated in vacuo and purified by flash-chromatography to give thelactone shown above as a colourless oil (22.0 mg, 0.19 mmol, 64% yield).[α]²⁰ _(D)=−16.5 (c 0.22, CHCl₃), Lit. [α]²⁷D=−24.8 (c=1.02, CHCl₃; 90%ee, (S)-enantiomer). ¹H NMR (400 MHz, CDCl₃): δ 4.49-4.41 (m, 1H), 4.28(td, J=10.5 and 3.5 Hz, 1H), 2.76-2.65 (m, 1H), 2.18-2.08 (m, 2H),2.00-1.90 (m, 1H), 1.61-1.49 (m, 1H), 1.09 (d, J=6.0 Hz, 3H). ¹³C NMR(100 MHz, CDCl₃): δ 171.0 (q), 68.4, 38.1, 30.5, 26.4, 21.3.

By obtaining the (−) enantiomer of the lactone it is certain (from acomparison with the literature value for the (S) enantiomer of thelactone [Irwin, A. J. & Jones, J. B. Asymmetric syntheses viaenantiotopically selective horse liver alcohol dehydrogenase catalyzedoxidations of diols containing a prochiral center. J. Am. Chem. Soc. 99,556-561 (1977).]) that the major diastereomer derived from the additionof 22 to 3 possessed (R)-stereochemistry at the new stereocenter (whichwas the 3-position of the glutaric anhydride).

Chromatogram of the thioesters 7a-b (derivatised as their o-nitrophenylesters for analysis via CSP-HPLC) from the reaction of 1 with 3 in thepresence of catalyst 18 under the conditions outlined in Table 1 entry19. The chromatogram clearly identifies (7a+ent-7a) as the majordiastereomer (89:11 dr) and allows the calculation of ee_(esterA),ee_(esterB), ee_(desymm), C and S.

Peak No Result Ret. Time (min) 1 0.441 13.880 2 44.742 15.063 3 5.06918.735 4 0.392 38.049

Calculations:

dr=(7a+ent-7a):(7b+ent-7b)

ee _(esterA)=100×[(7a−ent-7a)/(7a+ent-7a)]

ee _(esterB)=100×[(7b−ent-7b)/(7b+ent-7b)]

ee _(desymm)=100×[(7a+7b)−(ent-7a+ent-7b)]/[(7a+7b)+(ent-7a+ent-7b)]

ee _(thioester)=100×[(7a+ent-7b)−(7b+ent-7a)]/[(7a+ent-7b)+(7b+ent-7a)]

ee _(thiol)=determined by CPS-HPLC analysis, see chromatogram below.

C=100×ee _(thiol)/(ee _(thiol)+ee_(thioester))

Note: C calculated this way correlated precisely (within experimentalerror) with the conversion levels measured by ¹H NMR spectroscopy in allcases.

S=ln [(1−C)(1−ee _(thiol))]/ln [(1−C)(1−ee _(thiol))] or ln [1−C(1+ee_(thioester))]/ln [1−C(1−ee _(thioester))]

KR of Thiol 28 with Simultaneous Enantioselective Synthesis of a(R)-Pregabalin Precursor

A 20 mL reaction vial containing a stirring bar was charged with3-isobutylglutaric anhydride (4) (102.1 mg, 0.60 mmol) and 18 (47.2 mg,0.080 mmol). The reaction vial was flushed with argon and fitted with aseptum. MTBE was then injected (4.0 mL, 0.2M) and the solution cooled to−30° C. 28 (0.30 mmol) was added dropwise via syringe and the resultingsolution was stirred for 48 h. The mixture was the immediately loadedonto a column and the ‘slow reacting’ thiol enantiomer separated fromthe mixture by flash-chromatography (71.0 mg, 0.39 mmol, 98.7% ee asdetermined by CSP-HPLC after derivatisation as per general procedure B).The hemithioester product (29) was suspended in aq. NH₃ (3 mL) andstirred at room temperature for 4 h. The reaction was then diluted withCH₂Cl₂ (10.0 mL) and H₂O (5.0 mL) and transferred to a separatingfunnel. The organic and aqueous layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×10.0 mL). The combined organic layerswere then dried over MgSO₄ and the solvent removed under reducedpressure affording the ‘fast reacting’ (S)-thiol enantiomer (62.4 mg,0.35 mmol, 95.5% ee as determined by CSP-HPLC after derivatisation asper general procedure B) after flash chromatography. Conversion=50.8%, SFactor=226.

The aqueous layer was then acidified by addition of HCl (8 N) andextracted with EtOAc (5×15 mL). The combined organic phases were thendried over magnesium sulphate and the solvent was removed under reducedpressure to afford the desired hemiamide as a white solid (71.2 mg, 0.38mmol, 97.0% ee as determined by CSP-HPLC after transformation to thecorresponding o-nitrophenoxy ester, as per the procedure reportedbelow).

¹H NMR spectrum of (S)-30 (400 MHz, DMSO-d₆): δ 12.0 (br s, 1H), 7.27(s, 1H), 6.74 (s, 1H), 2.22-1.91 (m, 5H), 1.66-1.51 (m, 1H), 1.09 (appt, J 6.6, 2H), 0.81 (d, J 6.6, 6H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.3(q), 173.9 (q), 43.6, 40.2, 39.2, 30.1, 25.0, 23.2, 23.1. HRMS (m/z):[M+Na]⁺ calcd. for C₉H₁₇NO₃Na 210.1106. found, 210.1114.

The words “comprises/comprising” and the words “having/including” whenused herein with reference to the present invention are used to specifythe presence of stated features, integers, steps or components but donot preclude the presence or addition of one or more other features,integers, steps, components or groups thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination.

1. A method of resolving a mixture of stereoisomers of a thiolcomprising the step of preferentially acylating one thiol stereoisomerin the presence of a bifunctional organocatalyst; wherein thebifunctional organocatalyst is selected from the group consisting of:

wherein X can be O or S; Z can be a C₁ to C₅ carbon chain optionallycomprising at least one C—C unsaturated bond, and optionally substitutedone or more times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide andcombinations thereof; M can be H, OH, or OMe; B can be C₁-C₁₅ alkyl,C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅ heteroaryl or combinationsthereof, optionally substituted one or more times with at least one of ahalogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; R₁ andR₂ can be the same or different and may comprise C₁-C₁₅ alkyl, or R₁ andR₂ may together with N define a C₃-C₁₅ heterocyclic ring, wherein eachmay be optionally substituted one or more times with at least one of ahalogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; R₃ andR₄ can be the same or different and may comprise C₁-C₁₅ alkyl, or R₃ andR₄ may together define a C₃-C₁₅ cycloalkyl ring, a C₅-C₁₅ aryl ring, ora C₅-C₁₅ heteroaryl ring wherein each may be optionally substituted oneor more times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅alkyl and combinations thereof; and R₅ and R₆ can be the same ordifferent and may comprise C₁-C₁₅ alkyl, or R₅ and R₆ may togetherdefine a C₃-C₁₅ cycloalkyl ring, C₅-C₁₅ aryl ring, or a C₅-C₁₅heteroaryl ring wherein each may be optionally substituted one or moretimes with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone,C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyland combinations thereof.
 2. A method according to claim 1 wherein themixture of stereoisomers of the thiol is an enantiomeric mixture of thethiol.
 3. A method according to claim 1 wherein the thiols are selectedfrom the group consisting of primary thiols and secondary thiols.
 4. Amethod according to claim 1 wherein the bifunctional organocatalystcomprises a cinchona alkaloid.
 5. A method according to claim 4 whereinthe cinchona alkaloid is substituted with a urea, thiourea orsulfonamide functional group.
 6. A method according to claim 1 whereinthe step of acylating the thiol comprises reacting the thiol with anorganic anhydride.
 7. A method according to claim 6 wherein the organicanhydride is selected from the group consisting of:

wherein R₁ and R₂ are the same or different and are selected from thegroup consisting of C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀heteroaryl and combinations thereof, optionally substituted with atleast one of a halogen, cyano, or C₁-C₅ fluoroalkyl; R₃ and R₄ are thesame or different and are selected from the group consisting of H,C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀ heteroaryl andcombinations thereof, optionally substituted with at least one of ahalogen, cyano, or C₁-C₅ fluoroalkyl, such that at least one of R₃ andR₄ is H; R₅ and R₆ are the same or different and are selected from thegroup consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl,C₅-C₂₀ heteroaryl and combinations thereof, optionally substituted withat least one of a halogen, cyano, or C₁-C₅ fluoroalkyl; and n is 0-5. 8.A process for the preparation of enantioenriched3-(aminomethyl)-5-methylhexanoic acid comprising the steps of: i)preferentially acylating one thiol enantiomer of an enantiomeric mixtureof the thiol with 3-isobutylglutaric anhydride in the presence of abifunctional organocatalyst; wherein the bifunctional organocatalyst isselected from the group consisting of:

wherein X can be O or S; Z can be a C₁ to C₅ carbon chain optionallycomprising at least one C—C unsaturated bond, and optionally substitutedone or more times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide andcombinations thereof; M can be H, OH, or OMe; B can be C₁-C₁₅ alkyl,C₃-C₁₅ cycloalkyl, C₅-C₁₅ aryl, C₅-C₁₅ heteroaryl or combinationsthereof, optionally substituted one or more times with at least one of ahalogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; R₁ andR₂ can be the same or different and may comprise C₁-C₁₅ alkyl, or R₁ andR₂ may together with N define a C₃-C₁₅ heterocyclic ring, wherein eachmay be optionally substituted one or more times with at least one of ahalogen, cyano, CF₃, NO₂, C₁-C₅ ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyl and combinations thereof; R₃ andR₄ can be the same or different and may comprise C₁-C₁₅ alkyl, or R₃ andR₄ may together define a C₃-C₁₅ cycloalkyl ring, a C₅-C₁₅ aryl ring, ora C₅-C₁₅ heteroaryl ring wherein each may be optionally substituted oneor more times with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ketone, C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅alkyl and combinations thereof; and R₅ and R₆ can be the same ordifferent and may comprise C₁-C₁₅ alkyl, or R₅ and R₆ may togetherdefine a C₃-C₁₅ cycloalkyl ring, C₅-C₁₅ aryl ring, or a C₅-C₁₅heteroaryl ring wherein each may be optionally substituted one or moretimes with at least one of a halogen, cyano, CF₃, NO₂, C₁-C₅ ketone,C₁-C₅ ester, C₁-C₁₀ amide, C₁-C₅ sulfone, C₁-C₅ sulfoxide, C₁-C₅ alkyland combinations thereof; and ii) converting the thioester functionalgroup into an amine.
 9. A process according to claim 8 wherein the stepof converting the thioester functional group into an amine comprises:iii) aminolysis of the thioester functional group to yield an amide; andiv) subjecting the amide product of step iii) to a Hofmannrearrangement.
 10. A method according to claim 1, wherein the step ofacylating the thiol comprises reacting the thiol with an organicanhydride, wherein the organic anhydride is a prochiral anhydride andwherein acylation of the thiol with the prochiral anhydride in thepresence of the bifunctional organocatalyst proceeds withdesymmetrisation of the prochiral anhydride to afford a thioester.
 11. Amethod according to claim 10 wherein the prochiral anhydride is of thegeneral formula:

wherein R₃ and R₄ are the same or different and are selected from thegroup consisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl,C₅-C₂₀ heteroaryl and combinations thereof, optionally substituted withat least one of a halogen, cyano, or C₁-C₅ fluoroalkyl, such that atleast one of R₃ and R₄ is H; and n is
 1. 12. A method according to claim1, wherein the step of acylating the thiol comprises reacting the thiolwith an organic anhydride, wherein the organic anhydride is a mesoanhydride and wherein acylation of the thiol with the meso anhydride inthe presence of the bifunctional organocatalyst proceeds withdesymmetrisation of the meso anhydride to afford a thioester; whereinthe thioester is at least one of enantiomerically or diastereomericallyenriched.
 13. A method according to claim 12, wherein the meso anhydrideis of the general formula:

wherein R₅ and R₆ are the same and are selected from the groupconsisting of H, C₁-C₂₀ alkyl, C₃-C₂₀ cycloalkyl, C₅-C₂₀ aryl, C₅-C₂₀heteroaryl and combinations thereof, optionally substituted with atleast one of a halogen, cyano, or C₁-C₅ fluoroalkyl.
 14. A methodaccording to claim 10 wherein the thioester is at least one ofenantiomerically or diastereomerically enriched.
 15. A method accordingto claim 11 wherein the thioester is at least one of enantiomerically ordiastereomerically enriched.
 16. A method according to claim 10 whereinthe thiols are selected from the group consisting of primary thiols andsecondary thiols.
 17. A method according to claim 11 wherein the thiolsare selected from the group consisting of primary thiols and secondarythiols.